The Origin of the Prompt Emission for Short GRB 170817A: Photosphere Emission or Synchrotron Emission?

The first gravitational-wave event from the merger of a binary neutron star system (GW170817) was detected recently. The associated short gamma-ray burst (GRB 170817A) has a low isotropic luminosity (~1047 erg s−1) and a peak energy E p ~ 145 keV during the initial main emission between −0.3 and 0.4 s. The origin of this short GRB is still under debate, but a plausible interpretation is that it is due to the off-axis emission from a structured jet. We consider two possibilities. First, since the best-fit spectral model for the main pulse of GRB 170817A is a cutoff power law with a hard low-energy photon index ($\alpha =-{0.62}_{-0.54}^{+0.49}$), we consider an off-axis photosphere model. We develop a theory of photosphere emission in a structured jet and find that such a model can reproduce a low-energy photon index that is softer than a blackbody through enhancing high-latitude emission. The model can naturally account for the observed spectrum. The best-fit Lorentz factor along the line of sight is ~20, which demands that there is a significant delay between the merger and jet launching. Alternatively, we consider that the emission is produced via synchrotron radiation in an optically thin region in an expanding jet with decreasing magnetic fields. This model does not require a delay of jet launching but demands a larger bulk Lorentz factor along the line of sight. We perform Markov Chain Monte Carlo fitting to the data within the framework of both models and obtain good fitting results in both cases

Stapled peptide PROTAC induced significantly greater anti-PD-L1 effects than inhibitor in human cervical cancer cells

IntroductionImmune checkpoint inhibitors (ICIs) are monoclonal antibodies that target immune checkpoints that suppress immune cell activity. Low efficiency and high resistance are currently the main barriers to their clinical application. As a representative technology of targeted protein degradation, proteolysis-targeting chimeras (PROTACs) are considered to have potential for addressing these limitations.MethodsWe synthesized a stapled peptide-based PROTAC (SP-PROTAC) that specifically targeted palmitoyltransferase ZDHHC3 and resulted in the decrease of PD-L1 in human cervical cancer cell lines. Flow cytometry, confocal microscopy, protein immunoblotting, Cellular Thermal Shift Assay (CETSA), and MTT assay analyses were conducted to evaluate the effects of the designed peptide and verify its safety in human cells.ResultsIn cervical cancer celllines C33A and HeLa, the stapled peptide strongly downregulated PD-L1 to < 50% of baseline level at 0.1 μM. DHHC3 expression decreased in both dosedependentand time-dependent manners. MG132, the proteasome inhibitor, can alleviate the SP-PROTAC mediated degradation of PD-L1 in human cancer cells. In a co-culture model of C33A and T cells, treatment with the peptide induced IFN-γ and TNF-α release in a dose-dependent manner by degrading PD-L1. These effects were more significant than that of the PD-L1 inhibitor, BMS-8.ConclusionsCells treated with 0.1 μM of SP-PROTAC or BMS-8 for 4 h revealed that the stapled peptide decreased PD-L1 more effectively than BMS-8. DHHC3-targeting SP-PROTAC decreased PD-L1 in human cervical cancer more effectively than the inhibitor BMS-8

Studies on modified limited-memory BFGS method in full waveform inversion

Full waveform inversion (FWI) is a non-linear optimization problem based on full-wavefield modeling to obtain quantitative information of subsurface structure by minimizing the difference between the observed seismic data and the predicted wavefield. The limited-memory Broyden-Fletcher-Goldfarb-Shanno (L-BFGS) method is an effective quasi-Newton method in FWI due to its high inversion efficiency with low calculation and storage requirements. Like other conventional quasi-Newton methods, the approximation of the Hessian matrix in the L-BFGS method satisfies the quasi-Newton equation, which only exploits the gradient and model information while the available objective function value is neglected. The modified quasi-Newton equation considers the gradient, model, and objective function information together. Theoretical analysis reveals that the modified quasi-Newton equation is superior to the conventional quasi-Newton equation as it achieves higher-order accuracy in approximating the Hessian matrix. The modified L-BFGS method can be obtained by using the modified quasi-Newton equation to modify the L-BFGS method. This modification improves the accuracy of the Hessian matrix approximation with little increase of calculation for each iteration. We incorporate the modified L-BFGS method into FWI, numerical results show that the modified L-BFGS method has a higher convergence rate, achieves better inversion results, and has stronger anti-noise ability than the conventional L-BFGS method

Comparative Transcriptomics and Proteomics of Atractylodes lancea in Response to Endophytic Fungus Gilmaniella sp. AL12 Reveals Regulation in Plant Metabolism

The fungal endophyte Gilmaniella sp. AL12 can establish a beneficial association with the medicinal herb Atractylodes lancea, and improve plant growth and sesquiterpenoids accumulation, which is termed “double promotion.” Our previous studies have uncovered the underling primary mechanism based on some physiological evidences. However, a global understanding of gene or protein expression regulation in primary and secondary metabolism and related regulatory processes is still lacking. In this study, we employed transcriptomics and proteomics of Gilmaniella sp. AL12-inoculated and Gilmaniella sp. AL12-free plants to study the impact of endophyte inoculation at the transcriptional and translational levels. The results showed that plant genes involved in plant immunity and signaling were suppressed, similar to the plant response caused by some endophytic fungi and biotroph pathogen. The downregulated plant immunity may contribute to plant-endophyte beneficial interaction. Additionally, genes and proteins related to primary metabolism (carbon fixation, carbohydrate metabolism, and energy metabolism) tended to be upregulated after Gilmaniella sp. AL12 inoculation, which was consistent with our previous physiological evidences. And, Gilmaniella sp. AL12 upregulated genes involved in terpene skeleton biosynthesis, and upregulated genes annotated as β-farnesene synthase and β-caryophyllene synthase. Based on the above results, we proposed that endophyte-plant associations may improve production (biomass and sesquiterpenoids accumulation) by increasing the source (photosynthesis), expanding the sink (glycolysis and tricarboxylic acid cycle), and enhancing the metabolic flux (sesquiterpenoids biosynthesis pathway) in A. lancea. And, this study will help to further clarify plant-endophyte interactions

Curing hemophilia A by NHEJ-mediated ectopic F8 insertion in the mouse

BACKGROUND: Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%). RESULTS: We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects. CONCLUSIONS: These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components

Identification of Dysregulated Complement Activation Pathways Driven by N-Glycosylation Alterations in T2D Patients

Diabetes has become a major public health concern worldwide, most of which are type 2 diabetes (T2D). The diagnosis of T2D is commonly based on plasma glucose levels, and there are no reliable clinical biomarkers available for early detection. Recent advances in proteome technologies offer new opportunity for the understanding of T2D; however, the underlying proteomic characteristics of T2D have not been thoroughly investigated yet. Here, using proteomic and glycoproteomic profiling, we provided a comprehensive landscape of molecular alterations in the fasting plasma of the 24 Chinese participants, including eight T2D patients, eight prediabetic (PDB) subjects, and eight healthy control (HC) individuals. Our analyses identified a diverse set of potential biomarkers that might enhance the efficiency and accuracy based on current existing biological indicators of (pre)diabetes. Through integrative omics analysis, we showed the capability of glycoproteomics as a complement to proteomics or metabolomics, to provide additional insights into the pathogenesis of (pre)diabetes. We have newly identified systemic site-specific N-glycosylation alterations underlying T2D patients in the complement activation pathways, including decreased levels of N-glycopeptides from C1s, MASP1, and CFP proteins, and increased levels of N-glycopeptides from C2, C4, C4BPA, C4BPB, and CFH. These alterations were not observed at proteomic levels, suggesting new opportunities for the diagnosis and treatment of this disease. Our results demonstrate a great potential role of glycoproteomics in understanding (pre)diabetes and present a new direction for diabetes research which deserves more attention

Semen cassiae Extract Inhibits Contraction of Airway Smooth Muscle

β2-adrenoceptor agonists are commonly used as bronchodilators to treat obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), however, they induce severe side effects. Therefore, developing new bronchodilators is essential. Herbal plants were extracted and the extracts’ effect on airway smooth muscle (ASM) precontraction was assessed. The ethyl alcohol extract of semen cassiae (EESC) was extracted from Semen cassia. The effects of EESC on the ACh- and 80 mM K+-induced sustained precontraction in mouse and human ASM were evaluated. Ca2+ permeant ion channel currents and intracellular Ca2+ concentration were measured. HPLC analysis was employed to determine which compound was responsible for the EESC-induced relaxation. The EESC reversibly inhibited the ACh- and 80 mM K+-induced precontraction. The sustained precontraction depends on Ca2+ influx, and it was mediated by voltage-dependent L-type Ca2+ channels (LVDCCs), store-operated channels (SOCs), TRPC3/STIM/Orai channels. These channels were inhibited by aurantio-obtusin, one component of EESC. When aurantio-obtusin removed, EESC’s action disappeared. In addition, aurantio-obtusin inhibited the precontraction of mouse and human ASM and intracellular Ca2+ increases. These results indicate that Semen cassia-contained aurantio-obtusin inhibits sustained precontraction of ASM via inhibiting Ca2+-permeant ion channels, thereby, which could be used to develop new bronchodilators

High Altitude test of RPCs for the ARGO-YBJ experiment

A 50 m**2 RPC carpet was operated at the YangBaJing Cosmic Ray Laboratory (Tibet) located 4300 m a.s.l. The performance of RPCs in detecting Extensive Air Showers was studied. Efficiency and time resolution measurements at the pressure and temperature conditions typical of high mountain laboratories, are reported.Comment: 16 pages, 10 figures, submitted to Nucl. Instr. Met

Gamma ray flares from Mrk421 in 2008 observed with the ARGO-YBJ detector

In 2008 the blazar Markarian 421 entered a very active phase and was one of the brightest sources in the sky at TeV energies, showing frequent flaring episodes. Using the data of ARGO-YBJ, a full coverage air shower detector located at Yangbajing (4300 m a.s.l., Tibet, China), we monitored the source at gamma ray energies E > 0.3 TeV during the whole year. The observed flux was variable, with the strongest flares in March and June, in correlation with X-ray enhanced activity. While during specific episodes the TeV flux could be several times larger than the Crab Nebula one, the average emission from day 41 to 180 was almost twice the Crab level, with an integral flux of (3.6 +-0.6) 10^-11 photons cm^-2 s^-1 for energies E > 1 TeV, and decreased afterwards. This paper concentrates on the flares occurred in the first half of June. This period has been deeply studied from optical to 100 MeV gamma rays, and partially up to TeV energies, since the moonlight hampered the Cherenkov telescope observations during the most intense part of the emission. Our data complete these observations, with the detection of a signal with a statistical significance of 3.8 standard deviations on June 11-13, corresponding to a gamma ray flux about 6 times larger than the Crab one above 1 TeV. The reconstructed differential spectrum, corrected for the intergalactic absorption, can be represented by a power law with an index alpha = -2.1 extending up to several TeV. The spectrum slope is fully consistent with previous observations reporting a correlation between the flux and the spectral index, suggesting that this property is maintained in different epochs and characterizes the source emission processes.Comment: Accepted for publication on ApJ